Method for brominating heterocyclic compounds



Patented Dec. 21, 1948 METHOD FOR BROMINATING HETERO- CYCLIC COMPOUNDS Ferdinand B. Zienty, St. Louis, and Lucas 1'. V

Kyrides, Webster Groves, Mo., assignors to Monsanto Chemical Company, St. Louis, Mo., a corporation oi Delaware Nd Drawing. Application July 29, 1944, Serial No. 547,276

11 Claims. 1

This invention relates to certain brominated heterocyclic compounds and more particularly to a method of brominating certain heterocyclic compounds and to certain new and valuable mono bromo amino substituted heterocyclic compounds containing nitrogen and sulfur or selenium and their corresponding sulfanilyl derivatives.

The substitution of bromine for hydrogen in many heterocyclic compounds is accomplished.

generally by adding bromine to a cooled mixture of the heterocyclic compound and an acid such as sulfuric acid, maintaining the reaction mixture cool during the reaction, and recovering the brominated product substantially at the temperature of the reaction or at a lower temperature. These low temperature procedures were employed prior to the present invention presumably because decomposition of the desired product was expected to take place at higher temperatures. However, there are instances in which the bromination at the lower temperatures results in products other than those which are desired from the reaction. For example, while 2-amino-4-methylthiazole may be brominated and the resulting 2-amino-4- methyl-5-bromothiazole' recovered at the lower temperatures, we have found that the bromination of 2-aminothiazole according to this procedure results in a product which has two ionizable bromine residues per molecule, as evidenced by titration with a standard silver nitrate solution. Moreover, the yields were poor, and the product failed to react satisfactorily with N- acetyl sulfanilyl chloride, producing large amounts "of tar.

The object of this invention is to provide a novel bromination procedure for substituting bromine for hydrogen in the ring structure of certain heterocyclic compounds.

A further object is to provide a novel process for brominating 2-aminothiazole and its derivatives.

Another object is to provide certain novel brominated amino-substituted 5-membered heterocyclic compounds.

Another object is to provide certain novel sultanilyl derivatives of certain brominated aminosubstituted fi-membered heterocyclic compounds.

Another object is to provide a novel brominated 2-am inothiazole.

Another object is to provide a novel sulfanilyl bromo derivative of z-aminothiazole.

Other objects will be apparent from the following description and examples. v

According to the present invention, generally stated, certain heterocyclic compounds may be brominated by heating a mixture of the compound with an acidic substance or an acid, such as, hydrobromic acid, hydriodic acid, hydrochloric acid, or sulfuric acid, and water to the temperature of refluence of the mixture and thereupon slowly adding an equivalent amount of bromine to the mixture. The reaction is exothermic, and the temperature of the reaction mixture is maintained at reflux temperature during the reaction substantially without the aid of external heat. When all of the bromine has been added, and the reaction has subsided, the reaction mixture is cooled with agitation, for example to room temperature. The product is isolated from the reaction mixture by any desired method; for example, when the product separates out on cooling to room temperature, the product may be filtered oif and air-dried. If the product remains in solution after cooling to room temperature, the solution may be evaporated to induce a precipi-' tation oi. the product. If the product is precipitated while the solution is hot or at the boiling point, it may be desirable to filter the solution while it is hot to eifect a more eflicient removal of impurities dissolved in the mother liquor.

The bromination process of the present invention is applicable to the bromination of an oleflnic carbon atom or 5-membered amino-substituted heterocyclic compounds which contain in the ring structure at least one nitrogen atom, at least one sulfur or selenium atom and a formation in the ring represented by and which are stable in the presence of acids or acidic substances. Someoi' the heterocyclic compounds to which the process of the present invention applies are the aminothiazoles, the aminoselenazoles, the 4-alkyl and 4-alkenyl-aminothiazoles and aminoselenazoles, the alkyl aminothiazoles and aminoseienazoles,'2-amino-1,3,4-thiadiazole and 2-alkyl-amino-1,3,4-thiadiazoles. The resulting mono-bromo compounds are useful as anti-bacterial and anti-protozoa! agents and as intermediates for the preparation of pharmaceuticals, dyestufls, textile treating agents and fungicides. The N-sulfanilyl derivatives of these compounds are of particular interest in combating micro-organisms.

- When the process of the presentinventionis applied. to the bromination of Z-aminothia'zole, the product recovered from the reaction mixture OFFICE 1 Y drobromide.

. is 2-o-5-brorhothiazole hydrobromide, having the formular N--CH HBr-HcN- LB! The melmng point of the crude product as recovered from the reaction mixture was 140- 142 C., and the melting point of the product after one recrystallization from water was 141- 142 C. The melting point of the product after two additional recrystallizations from water was 144-145 C. The free base is obtained by neutralization of the hydrobromide with an alkali.

The product resulting from the bromination of 2-aminothiazole by the method of the present invenflon has been found to react in the free base form with N-acetyl-sulfanilyl chloride. to produce the novel compound, 2-N -acetyl-sulfanilamido-fi-bromothiazcle. This compound is then hydrolyzed with alkali to yield the compound 2- do-fi-bromothiazole, having the for- H N-CH acorn a-..

This compound has been found to possess outstanding utility as an anti-bacterial and antipro agent in combating micro-organisms in vivo in instances in which many sulfa drugs are five.

As an alternative embodiment of the process of the present invention, the bromination may be conduct& at relatively low temperatures, for example, 5 to 55 C., and the resulting reaction ":1 then heated to the boiling point and boilm for a short time, for example several minutes.- The bromination may be conducted at temperatures just above the freezing point of the reaction mixture, which in some instances may be as low as 6., or even lower. Following the bromination operation, the reaction mixture is then heated to the boiling point for a short time.

As afurther alternative embodiment of the pm of the present invention, the addition of bromine to the reaction mixture may be effected during the operation of heating the solution to the boiling point, proceeding cautiously, however, in view of the fact that the bromination reaction is exothermic.

The following examples will serve to illustrate the novel process and products of the present invention. These examples are to be construed merely as illustrative and not as limiting the scope of the invention, which is applicable to the brominaizion of heterocyclic compounds of the type hereinhefore described.

Example I A of 150 g. (1.5 moles) of 2-aminothiazole, 300 cc. of water and 250 g. of 48% hydrobromic acid (1.5 moles) was'heatcd to reflux temperature, and 240 g. (1.5 moles) (77.4 cc.) of bromine was added to the mixture over a period of about 35 minutes. The bromination reaction was exothermic, since the batch remained at reflux temperature without external heating during the addition of the bromine. When all the bromine had been added. the mixture was cooled to 25 C. with stirring and the crystals which separated out were filtered and air-dried. Yield, 180 gof pink crystals; melting point 140-14? C. The product was 2-amino-5-bromothiazole by- This salt was recrystallized from water, using 160 cc. and 5.0 g. of decolorizing charcoal for every g. of 2-amino-5-bromothlazole hydrobromide. The filtered liquor was treated with 0.1 g. of sodium hydrosulfite and cooled to 15C. The crystals which separated were filtered off and dried. The melting point was 141-142 C. The 2-amino-5-bromothiazole hydrobromide was found to contain molecule of water of crystallization as shown by titration, using the Karl Fischer method. Assay, 100.6% of the hydrate by titration with silver nitrate. Non-ionizable bromine 30.1%; theory 30.8%. Ionizable bromine 30.2%; theory 30.8%. The 2-amino-5-bromothiazole hydrobromide is useful as an anti-bacterial agent, and as an intermediate in the preparation of dyestufi's, textile treating agents, fungicides, insecticide toxicants and Example II A slurry of 100 g. of wet recrystallized Z-amino- 5-bromothiazole,prepared according to the meth- 0d of Example I and containing less than 5% moisture, and 400 cc. of water was stirred and cooled below 5 C. A solution of 32.0 g. of 50% sodium hydroxide in 50 cc. of water was added to this solution by means of a dropping funnel, the temperature of the batch being maintained below 5 C. The mixture was just alkaline to phenolphthalein at the end of the neutralization; 0.3 g. of sodium hydrosulfite was added, and the mixture was stirred for 1 hr. at 5 C. The graybrown crystals of 2-amino-5-bromothiazole were filtered oii and dried in the air. Melting point of the crude product, 102-103 C., forming a black melt. Yield, 63.2 g. (98%). The free base 2- amino-5-bromothiazole was recrystallized from water, using 300 cc. of water and 0.4 g. of decolorizing charcoal for each 10 g. of the amine.

Recovery, 81%; melting point 105-106 C. The

2-amino-5-bromothiazole is useful as an antibacterial agent and as an intermediate in the preparation of dyestufis, pharmaceuticals, textile treating agents, fungicides and insecticides.

Example III 300 cc. of anhydrous pyridine was cooled to 5 C., and 25.6 g. (0.142 mole) of 2-amino-5-bromothiazole, prepared according to the method of Example II, was added. A solution of the amine in, pyridine was formed when the mixture was agitated. 40 g. (20% excess) of N-acetyl-sulfanilyl chloride was added to the solution over a period of about 15 keeping the temperature of the batch below 5 C. The mixture was stirred for about 15 hrs. at a temperature below 5 C. Water was added, pyridine was distilled out under reduced pressure, and the precipitate was filtered off and washed thoroughly with water. After drying at 60 C. the product weighed 30.7 g. (69% yield). The product was 2-N acetylsulfanilamido-5-bromothiazole. It is useful as an anti-bacterial agent and in the preparation of fungicides and in the treatment of textiles.

Example IV A solution of 33.8 g. (0.01 mole) of 2-N -acetylsulfanilamido-S-bromothiazole,' prepared according to the method of Example III, in 520 cc. of 2% sodium hydroxide was refluxed for 1% hrs. 2 g. of decolorizing charcoal were added, and the mixture was filtered hot. The filtrate was cooled to 30 C., and a solution of 16 cc. of concentrated filtered off and dried.

hydrochloric acid in 100 cc. of water was added to the filtrate over a period of about 1 hr. until the mixture was acid to litmus. Thecrystalline product was filtered off, washed with water and dried. The product was 2-sulfanilamido-5-bromothiazole. Weight, 26.1 g. (87% yield). The 2-sulfanilamido-5-bromothiazole was purified by recrystallization from 50% acetone; yellow crystals. The melting point was indistinct; decomposition took place above 190 C. Assay, 101% by alkali titration in acetone, using a phenolphthalein indicator. The product is useful as an antibacterial agent, anti-protozoal agent, fungicide and textile treating agent.

Example V A solution of 15 g. of sulfuric acid in 100 cc. of water was prepared and cooled to 25 C. To this solution 25 g. of z-aminothiazole was added. When the solid material was dissolved, the temperature of the resulting solution was raised to 55 C. and held at that temperature by means of external cooling while 36 g. of bromine (11.5 cc.) was slowly added. After the reaction was complete, the solution was heated to boiling and boiled for approximately 2 min. to remove excess bromine. Thereafter the solution was cooled approximately to room temperature, or 25 to 30 C., and allowed to stand at that temperature. Crystals of 2-amino-5-bromothiazole hydrobromide separated from the solution and were filtered off and dried. Yield 6.5 g.; melting point 139141 C. The filtrate was cooled to a temperature slightly below 5 C., whereupon a second crop of crystals was obtained. These were filtered of! and dried, Melting point 140-142 C. The remaining liquid was evaporated to a small volume and cooled. A third crop of crystals was obtained. Melting 7 ,point 139-140 C. Total yield 13.9 g. or 23%.

Nonionizable bromide 30.2%; theory 30.8%. Ionizable bromide 29%; theory 30.8%. Melting point after one crystallization from water, 141- 142 (2.; melting point after two additional recrystallizations from water, 144-145 C.

Example VI A solution or 25 g. of sulfuric acid in 20 cc. of water was cooled to 30C. To this solution 50 g.

, of 2-amino-thiazole was added and dissolved therein. The temperature ofthe solution was brought to 30 C. and held at that point by 'bromine were added over a 2-hr. period, the temperature being maintained at 30 C. The solution was evaporated at room temperature to a small volume. Crystals separated out and were Yield 63 g. Ionizable bromine 58%; theory for 2-arnino-5-bromothiazole hydrobromide 30.8%. This example illustrates the result of applying the customary procedure in endeavoring to brominate 2-aminothiazole. The melting point of the resulting product was found to be below 115 C. Attempts to form the N-acetyl-sulfanilyl derivative of the product were unsuccessful. However, if the bromination reaction mixture is heated to the boiling point for several minutes before recovery of the product, the desired 2-amino-5-bromothiazole compound is obtained.

Example VII z-aminoselenazole may be brominated according to the process described in Example I. The

resulting product is 2-amino-5-bromoselenazole hydrobromide, having the formula:

HO -N Br- -NHLHBI Example VIII The process described in Example I may be repeated using Z-methylaminothiazole in place of 2-aminothlazole. The resulting product is 2-methylamino-5-bromothiazole hydrobromide, having the formula:

Other alkyyl and. alkenyl residues having from 1-22 carbon atoms may be substituted for the methyl group on the amino residue, for example, the ethyl, isopropyl, butyl, amyl, octyl, decyl, dodecyl, heptadecenyl and eicosyl residues.

Example IX The process of Example I may be repeated using 2-amino-1,3,4-thiadiazole. The resulting product is 2-amino-5-bromo-1,3,4-thiadiazole, having the formula:

NN Br-g E-NHl-HBI ExampleX Z-methylamino-1,3,4-thiadiazole maybe brominated according to the method of Example I. The resulting product is 2-methylamino-5- bromo-1,3,4-thiadiazole hydrobromide, having the formula:

Example XI 2-amino-4-methylthiazole may be brominated according to the method of Example I. The resulting product is 2-amino-4methyl-5-bromothiazole hydrobromide, having the formula:

2-amino-4-ethylselenazole may be brominated according to the process described in Example II. The resulting product is 2-amino-4-ethyl-5- bromoselenazole hydrobromide, having the formula:

CrHs-C N Br- N H:.HBr

Other alkyl and alkenyl residues having from 1-22 carbon atoms may be substituted for the ethyl group on the ring, forexample, the methyl, isopropyl, butyl, amy1, octyl, decyl, dodecyl, heptadecenyl and eicosyl residues.

Example XIII The process of Example I may be repeated, using 2-methylamlno-4-amylthiazole in place of 2-aminothiazole. The resulting product is 2-methyl-amino-4-amyl-5-bromothiazole hydrobromide, having the formula:

Other alkyl and alkenyl residues having from 1-22 carbon atoms may be substituted for the my] residue on the ring structure and the methyl residue on the amino group, for example, the ethyl, isopropyl, butyl, octyl, decyl, dodecyl, heptadecenyl and eicosyl residues.

Example XIV The free base derivatives of the bromo compounds described in Examples VII-XIII may be prepared by alkalinization of the hydrobromide salts according to the method of Example II. The N -acetyl-sulfanilamido derivatives of the free base bromo compounds corresponding to the hydrobromide salt compounds of Examples VII- IHII may be prepared according to the method of Example 111. The acetyl residue in the resulting compounds may be hydrolyzed off by the method of Example IV. The resulting 2-sulianilamido bromo compounds are:

Example VII.2-sulfanilamido-5-bromoselenazole, having the formula:

. r r N---CH HiNOSOr-N- -Br Example VIII.-N'-methyl-2-sulfanilamido-5- bromothiazole, having the formula:

H3 NCH v s Emample IX.-2-sulfanilamido-5-bromo-1,3,4- thiadiazole, having the formula:

H NN

Example X.N"-methyl 2-sulfanilamido 5- bromo-1,3,4-thiadiozole, having the formula:

The sulfanilamido bromo derivatives of the com-.

mation in the ring represented by and which compound is stable in acidic solutions, comprising, heating said compound in water in the presence of an acid to the boiling point of the mixture, adding bromine slowly to the mixture and recovering the brominated product from the reaction mixture.

The process of substituting bromine for hy I drogen on an olefinic carbon atom in the rim structure of a 5-membered amino-substituted heterocyclic compound which contains in the ring structure at least 1 nitrogen atom, at least 1 atom of an element selected from the group consisting of sulfur and selenimn, and a formation in the ring represented by and recovering the brominated product from the reaction mixture.

3. The process of substituting bromine for hydrogen on an olefinic carbon atom in the ring structure of' a 5-membered mu n- I heterocyclic compound which contains in the ring structure at least 1 nitrogen atom, at lewt 1 atom of an element selected from the group consisting of sulfur and selenium, and a formav tion in the ring represented by and which compound is stable in acidic aqueous solutions, comprising, heating said compoimd in water in the presence of hydrobromic acid substantially to the boiling point of the mixture, adding bromine slowly to the mixture, cooling the resulting reaction mixture and recovering the brominated product from the reaction mixture.

4. The process of substituting bromine for hydrogen on an olefinic carbon atom in the ring structure of a S-membered heterocyclic compound which contains in the ring structure at least -1 nitrogen atom, at least 1 atom of an element selected from the group consisting of sulfur and selenium, and a formation in the ring represented by and which compound is stable in acidic aqueous solutions, comprising, heating said compound in water in the presence of an acid and bromine substantially to the boiling point of the mixture, and recovering the brominated product from the reaction mixture.

5. The process of substituting bromine for hydrogen on a carbon atom of an aminothiazole, comprising, heating said compound in water in the presence of an acid substantially to the boiling point of the mixture, adding bromine slowly to the mixture, cooling the resulting reaction mixture and recovering the brominated product from the reaction mixture.

6. The process of substituting bromine for hydrogen on a carbon atom of an aminothiazole, comprising, adding bromine slowly to a dispersion of said compound in water in the presence of an acid, heating the resulting reaction mix- 'minated product from the reaction mixture.

ture to the boiling point of the mixture and recovering the brominated productirom the reaction mixture.

7. The process of substituting bromine for hydrogen on the 5 carbon atom of 2-aminothiazole, comprising, heating said compound in water in the presence of an acid substantially to the boiling point; of the mixture, adding bromine slowly to the mixture and recovering the brominated product'from the reaction-mixture.

8. The process of substituting bromine for hydrogen on the 5 carbon atom of 2-aminothiazole, comprising, heating said compound in water in the presence of hydrobromic acid substantially to the boiling point of the mixture, adding bromine slowly to the mixture, cooling the resulting reaction mixture anii recovering the brominated product from the reaction mixture.

9. The process of substituting bromine for hydrogen on a carbon atom of an aminoselenazole, comprising, heating said compound in water in the presence or an acid substantially to the 10. The process of substituting bromine for hydrogen on a. carbon atom of an amino-1,3,4- thiadiazole, comprising, heating said compound in water in the presence of an acid substantially to the boiling point of the mixture, adding bromine slowly to the mixture and recovering the brominated product from the reaction mixture. 11. The process of substituting bromine for hydrogen on the 5 carbon atom of 2-aminothiazole, comprising, heating said compound in ,water in the presence of an acid and bromine substantially to the boiling point of the mixture, and recovering the brominated product from the reaction mixture.

FERDINAND B. ZIENTY. LUCAS P. KYRIDES.

REFERENCES CITED The following references are of record inthe tile of this patent:

UNITED STATES PATENTS OTHER REFERENCES Chemical Abstracts, vol. 33, 1939, page 77829, citing Berichte,'72B, (1470-1476), 1939, 

